The theme of this program project is the investigation of selected cellular and biochemical events which may be instrumental in the malignant transformation of normal human urothelium into urothelial carcinoma. The processes we shall study- chromosomal/genetic loses in multistep transformation in vitro, carcinogen activity by target tissue, and target cell responsiveness to an ubiquitous growth factor - all have strong evidence linking them to fundamental events in urothelial cell tumorigenesis. Overall Objective: To elucidate how normal cellular components and events become altered and/or """"""""take advantage"""""""" of their unique environment, to contribute to the expression of the transformed phenotype.
Specific Aims : To test the following hypotheses: *Chromosomal/genetic losses correlate with tumorigenic transformation in vitro and neoplastic progression of human uroepithelial cells. *N-acetylases and deacetylases play a determinate role in susceptibility to bladder cancer. *Enzymatic activation and/or inactivation of arylamine bladder carcinogens by human urothelium occurs, and influences an individual's susceptibility for developing bladder cancer. *Alterations in post-ligand binding events occur in transformed transitional epithelial cells which enable them, but not their normal counterparts, to be stimulated by a mitogen to which they are both continually exposed - epidermal growth factor. These investigations will provide insights into the processes of neoplastic development and growth, and may yield information of importance for clinical classification, early detection, prognosis, prevention and treatment of urothelial cancers.
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